Xu, Lanting, Zhu, Jiazhou, Shen, Xiaodong, Chai, Jiashuang, Shi, Lei-1, Wu, Bin, Li, Wei and Ma, Dawei (2024) Novel 6-Hydroxy Picolinohydrazide Ligands Promoted a Highly Efficient Cu(I)-Catalyzed Hydroxylation Reaction with Water. Angewandte Chemie. International edition.

Abstract

Hydroxylated (hetero)arenes are prevalent in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively facilitated. L31 (6-HPA-DMCA) demonstrated high efficiency in bromide substrates, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C, or under near-room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100°C. These represent the currently lowest catalyst loading and temperature for copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

Item Type:	Article
Date Deposited:	18 Sep 2024 00:45
Last Modified:	18 Sep 2024 00:45
URI:	https://oak.novartis.com/id/eprint/54402